The prognosis for glioblastoma multiforme (GBM) is extremely poor. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize GBM responses to cytotoxic and targeted agents is therefore urgently needed. CD44 is a major cell surface receptor for hyaluronan (HA) and a cancer stem cell marker, and has been implicated in cancer progression. However, little is known about its contributions to GBM progression and to the responses of GBM cells to chemo- and targeted therapies and about the major downstream signaling pathway that mediates the pro-tumor effect of CD44. We show that CD44 is up regulated in malignant gliomas and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. We first demonstrate that CD44 antagonists display potent anti-GBM efficacy in mouse models and that CD44 functions upstream of mammalian Hippo signaling pathway. Furthermore, CD44 promotes GBM cell resistance to reactive oxygen species- and cytotoxic agent-induced stress and apoptosis by attenuating activation of the Hippo pathway kinases MST1/2 and Lats1/2. We also show that CD44 enhances the growth signals derived from ErbB and c-Met receptor tyrosine kinases (RTKs). Based on these results, we hypothesize that CD44 antagonists inhibit GBM progression and sensitize GBM responses to chemo- and targeted therapies by inhibiting GBM cell survival through enhancing activation of the Hippo signaling pathway and inhibiting the growth signals derived from ErbB/c-Met RTKs. We further hypothesize that CD44 is a prime target for GBM therapy and its antagonists are efficacious when used as single agents and/or combination with chemotherapeutic agents and pharmacological inhibitors of erbB and c-Met RTKs in the GBM mouse models. Three specific aims are proposed. Aim 1 is to establish that CD44 antagonists, a variety of soluble CD44-Fc fusion proteins, display anti- glioma activity, sensitize GBM response to chemo- and targeted therapies in vivo. Aim 2 is to establish that the chemosensitizing effect of CD44 antagonists in vivo is achieved by enhancing activation of Hippo signaling pathway. Finally, aim 3 is to establish that hsCD44-Fc fusion proteins achieve their anti-glioma effect and sensitize GBM response to the targeted therapies, at least partially, through inhibiting activities of erbB and c-Met RTKs. The results from proposed experiments will establish CD44 as a prime therapeutic target for GBM and demonstrate potent therapeutic efficacies of the newly developed CD44 antagonists as single agents and/or in combinations with chemo- and other targeted therapies in preclinical GBM models. These results may lead to better clinical outcome and longer lasting clinical benefit for GBM patients in the future. Therefore, this proposal has high biological and clinical relevance and significance, and translational potential.